Riboflavin

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Riboflavin
Riboflavin.svg
Riboflavin-3d-balls.png
Chemical structure
Clinical data
Trade namesMany[1]
Other namesvactochrome, lactoflavin, vitamin G[2]
AHFS/Drugs.comMonograph
License data
Routes of
administration
By mouth, intramuscular, intravenous
ATC code
Legal status
Legal status
  • US: Dietary supplement
Pharmacokinetic data
Elimination half-life66 to 84 minutes
ExcretionUrine
Identifiers
  • 7,8-Dimethyl-10-[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]benzo[g]pteridine-2,4-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E numberE101, E101(iii) (colours) Edit this at Wikidata
CompTox Dashboard (EPA)
ECHA InfoCard100.001.370 Edit this at Wikidata
Chemical and physical data
FormulaC17H20N4O6
Molar mass376.369 g·mol−1
3D model (JSmol)
  • c12cc(C)c(C)cc1N=C3C(=O)NC(=O)N=C3N2C[C@H](O)[C@H](O)[C@H](O)CO
  • InChI=InChI=1S/C17H20N4O6/c1-7-3-9-10(4-8(7)2)21(5-11(23)14(25)12(24)6-22)15-13(18-9)16(26)20-17(27)19-15/h3-4,11-12,14,22-25H,5-6H2,1-2H3,(H,20,26,27)/t11-,12+,14-/m0/s1 ☒N
  • Key:AUNGANRZJHBGPY-SCRDCRAPSA-N

Riboflavin, also known as vitamin B2, is a vitamin found in food and consumed as a dietary supplement.[1][3] It is essential to the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. These coenzymes are involved in energy metabolism, cellular respiration, antibody production, growth and development and having essential roles in the maintenance of healthy skin, hair, and nails. The coenzymes are also involved in the metabolism of other vitamins – niacin, vitamin B6, and folate.[3][4]

Food sources include eggs, green vegetables, milk and other dairy products, meat, mushrooms, and almonds.[3] Some countries require its addition to grains.[3][5] As a supplement, it is used to prevent and treat riboflavin deficiency, may be given by mouth or injection, and is well-tolerated.[1][3] Riboflavin deficiency is rare, although it does occur in time of chronic or acute under-nutrition, usually accompanied by deficiencies of other vitamins and nutrients. Consumption in excess of requirements is not stored; it is either not absorbed, or absorbed and quickly excreted in urine, causing the urine to take on a bright yellow tint.[6]

Riboflavin was discovered in 1920, isolated in 1933, and first synthesized in 1935.[2]

Definition[edit]

Riboflavin, also known as vitamin B2 is a water-soluble vitamin, one of the B vitamins.[3][7][8] The "flavin" portion of the molecule is combined with a ribose-like part derived from ribulose 5-phosphate to become riboflavin.[4] Bacteria in the large intestine produce riboflavin which is then absorbed in amounts determined by the diet, as more riboflavin is produced following consumption of vegetables compared to a diet mainly of meats.[3]

Functions[edit]

Riboflavin is essential to the formation of two major coenzymes, flavin mononucleotide (FMN, also called riboflavin-5’-phosphate) and flavin adenine dinucleotide (FAD).[3][9] FMN and FAD are involved in energy metabolism, cell respiration, antibody production, growth, and development, having essential roles in the maintenance of healthy skin, hair, and nails.[4][9] Riboflavin is essential for the metabolism of steroids, carbohydrates, protein, fats, circulating toxins, and drugs.[3][4] FAD contributes to conversion of tryptophan to synthesize niacin (vitamin B3).[4] The conversion of vitamin B6 to the coenzyme pyridoxal 5’-phosphate requires FMN.[4] Riboflavin is involved in maintaining normal circulating levels of the amino acid, homocysteine; in riboflavin deficiency, homocysteine levels increase, elevating the risk of cardiovascular diseases.[4]

Redox reactions[edit]

Redox reactions are cellular processes that involve transfer of electrons, which is the energy-producing process in the cells of living organisms.[4] The riboflavin coenzymes, FMN and FAD, participate in redox reactions in most metabolic pathways.[3][4] FAD is essential for activity in the electron transport chain, which supplies energy in cells.[4][9]

FAD catalyzes the activity of glutathione reductase, an essential enzyme in formation of the endogenous antioxidant, glutathione.[4][9]

Micronutrient metabolism[edit]

Riboflavin, FMN, and FAD are involved in the metabolism of niacin, vitamin B6, and folate.[4][9] The synthesis of the niacin-containing enzymes, NAD and NADP, from tryptophan involves the FAD-dependent enzyme, kynurenine 3-monooxygenase.[4] Dietary deficiency of riboflavin can decrease the production of NAD and NADP, thereby promoting niacin deficiency.[4] Conversion of vitamin B6 to its coenzyme, pyridoxal 5'-phosphate synthase, involves the enzyme, pyridoxine 5′-phosphate oxidase, which requires FMN.[4][9] An enzyme involved in folate metabolism – 5,10-methylenetetrahydrofolate reductase – requires FAD to form the amino acid, methionine, from homocysteine.[4]

Riboflavin deficiency appears to impair the metabolism of the essential dietary mineral, iron, which is essential to the production of hemoglobin and red blood cells.[4] Alleviating riboflavin deficiency in people who are deficient in both riboflavin and iron improves the effect of iron supplementation for treating iron-deficiency anemia.[4]

Synthesis[edit]

Biosynthesis[edit]

The biosynthesis of one riboflavin molecule requires ribulose 5-phosphate and guanosine triphosphate (GTP) as substrates.[9] The imidazole ring of GTP is hydrolytically opened, yielding a 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione 5'-phosphate by a sequence of deamination, side chain reduction and dephosphorylation. Condensation of this molecule with 3,4-dihydroxy-2-butanone 4-phosphate obtained from ribulose 5-phosphate creates an unstable intermediate that converts to 6,7-dimethyl-8-ribityllumazine.[4][9]

Dismutation of two of this molecule, through action of the enzyme riboflavin synthase, yields riboflavin and a molecule of 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione, which is recycled in the biosynthetic pathway.[8][9]

Mech 1.jpg Mech 2.jpg Mech 3.jpg Mech 4.jpg

Industrial synthesis[edit]

Large cultures of Micrococcus luteus growing on pyridine (left) and succinic acid (right). The pyridine culture has turned yellow from produced riboflavin.[10]

The industrial scale production of riboflavin uses various microorganisms, including filamentous fungi such as Ashbya gossypii, Candida famata and Candida flaveri, as well as the bacteria Corynebacterium ammoniagenes and Bacillus subtilis.[11] The last organism, genetically modified to both increase the production of riboflavin and to introduce an antibiotic (ampicillin) resistance marker, is employed at a commercial scale to produce riboflavin for feed and food fortification. Riboflavin is sometimes overproduced, possibly as a protective mechanism, by some bacteria in the presence of high concentrations of hydrocarbons or aromatic compounds. One such organism is Micrococcus luteus (American Type Culture Collection strain number ATCC 49442), which develops a yellow color due to production of riboflavin while growing on pyridine, but not when grown on other substrates, such as succinic acid.[10]

Chemical properties[edit]

Riboflavin is a yellow-orange crystalline powder having a slight odor and bitter taste.[9] It is soluble in water and sodium chloride solutions, and is not soluble in lipid solvents.[9] In solution or during dry storage as a powder, riboflavin is heat stable if not exposed to light.[9] When heated to decompose, it releases toxic fumes containing nitric oxide.[9]

Medical uses[edit]

Cornea thinning[edit]

Corneal ectasia is a progressive thinning of the cornea; the most common form of this condition is keratoconus. Corneal collagen crosslinking, causing an increase in corneal stiffness, is achieved by applying a riboflavin solution topically, then exposing to ultraviolet A light.[12][13]

Migraine[edit]

In its 2012 guidelines, the American Academy of Neurology included high-dose riboflavin (400 mg) as "probably effective and should be considered for migraine prevention,"[14] a recommendation also provided by the UK National Migraine Centre.[15] A 2017 review reported that daily riboflavin taken at 400 mg per day for at least three months may reduce the frequency of migraine headaches in adults.[16] Research on high-dose riboflavin for migraine prevention or treatment in children and adolescents is inconclusive, and not recommended.[1][3][17]

Food coloring[edit]

Riboflavin is used as a food coloring (yellow-orange crystalline powder),[9] and is designated with the E number, E101, in Europe for use as a food additive.[18]

Dietary recommendations[edit]

United States
Age group (years) RDA for riboflavin (mg/d)[7] Tolerable upper intake level[7]
Infants 0–6 months 0.3* ND
Infants 6–12 months 0.4*
1–3 0.5
4–8 0.6
9–13 0.9
Females 14–18 1.0
Males 14–18 1.3
Females 19+ 1.1
Males 19+ 1.3
Pregnant females 14–50 1.4
Lactating females 14–50 1.6
European Food Safety Authority
Age group (years) Adequate Intake of riboflavin (mg/d)[19] Tolerable upper limit[19]
7–11 months 0.4 ND
1–3 0.6
4–6 0.7
7–10 1.0
11–14 1.4
15–17 1.6
18+
Australia and New Zealand
Age group (years) Adequate Intake of riboflavin (mg/d)[20] Upper level of intake[20]
0–6 months 0.3* ND
7–12 months 0.4*
1–3 0.5
4–8 0.6
9–13 0.9
Females 14–70 1.1
Males 14–70 1.3
Females >70 1.3
Males >70 1.6
Pregnant females 14–50 1.4
Lactating females 14–50 1.6
* Adequate intake for infants, no RDA/RDI yet established[7]

The National Academy of Medicine (then the U.S. Institute of Medicine [IOM]) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for riboflavin in 1998. The current EARs for riboflavin for women and men ages 14 and up are 0.9 mg/day and 1.1 mg/day, respectively; the RDAs are 1.1 and 1.3 mg/day, respectively. RDAs are higher than EARs so as to identify amounts that will cover people with higher than average requirements. RDA for pregnancy is 1.4 mg/day. RDA for lactation is 1.6 mg/day. For infants up to 12 months the Adequate Intake (AI) is 0.3–0.4 mg/day. and for children ages 1–13 years the RDA increases with age from 0.5 to 0.9 mg/day. As for safety, the IOM sets Tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of riboflavin there is no UL, as there is no human data for adverse effects from high doses. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).[7][21]

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL defined the same as in United States. For women and men ages 15 and older the PRI is set at 1.6 mg/day. PRI for pregnancy is 1.9 mg/day, for lactation 2.0 mg/day. For children ages 1–14 years the PRIs increase with age from 0.6 to 1.4 mg/day. These PRIs are higher than the U.S. RDAs.[22] The EFSA also reviewed the safety question and like the U.S., decided that there was not sufficient information to set an UL.[23]

Safety[edit]

In humans, there is no evidence for riboflavin toxicity produced by excessive intakes. Absorption becomes less efficient as doses increase, and what is absorbed in excess of requirements is excreted via the kidneys into urine (resulting in a bright yellow color).[21][7][8] When up to 400 mg of riboflavin per day for trial periods of 3–12 months was consumed orally for research on reducing frequency and severity of migraine headache, there were reports of abdominal pain and diarrhea in the treated subjects.[16]

Labeling[edit]

For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For riboflavin labeling purposes 100% of the Daily Value was 1.7 mg, but as of May 27, 2016, it was revised to 1.3 mg to bring it into agreement with the RDA.[24][25] A table of the old and new adult daily values is provided at Reference Daily Intake.

Sources[edit]

Food and beverages that provide riboflavin without fortification are milk, cheese, eggs, leaf vegetables, liver, kidneys, lean meats, legumes, mushrooms, and almonds.[4][7]

The milling of cereals results in considerable loss (up to 60%) of vitamin B2, so white flour is enriched in some countries by addition of the vitamin. The enrichment of bread and ready-to-eat breakfast cereals contributes significantly to the dietary supply of vitamin B2. Polished rice is not usually enriched, because the vitamin's yellow color would make the rice visually unacceptable to the major rice-consuming populations. However, most of the flavin content of whole brown rice is retained if the rice is steamed (parboiled) prior to milling. This process drives the flavins in the germ and aleurone layers into the endosperm. Free riboflavin is naturally present in foods along with protein-bound FMN and FAD. Bovine milk contains mainly free riboflavin, with a minor contribution from FMN and FAD.[26] Milk and yogurt contain some of the highest riboflavin content.[3]

Riboflavin is added to baby foods, breakfast cereals, pastas and vitamin-enriched meal replacement products.[3] It is difficult to incorporate riboflavin into liquid products because it has poor solubility in water, hence the requirement for riboflavin-5'-phosphate (E101a), a more soluble form of riboflavin.[9]

Fortification[edit]

As of 2021, 56 countries require food fortification of wheat flour or maize (corn) flour with riboflavin or riboflavin-5'-phosphate sodium. Most of these are in north and south America and southeast Africa. The amounts stipulated range from 1.3 to 5.75 mg/kg. An additional 16 countries, including India and China, have a voluntary fortification program. India stipulates 1.5 mg/kg for wheat flour.[27]

Assessing status[edit]

Total riboflavin excretion in healthy adults with normal riboflavin intake is about 120 micrograms per day, while excretion of less than 40 micrograms per day indicates deficiency.[3][28]

Although riboflavin levels in blood or urine are not routinely measured in healthy people, the erythrocyte glutathione reductase activity coefficient (EGRAC) is a reliable laboratory determination.[3][28] An EGRAC score of 1.2 or less indicates adequate riboflavin status, while 1.2–1.4 indicates marginal deficiency, and more than 1.4 indicates deficiency.[3][28] Fluorometric measurement of urinary riboflavin excretion over 24 hours is also used to assess riboflavin status, although it is less accurate for assessing chronic riboflavin status compared to EGRAC.[3] Riboflavin excretion rates decrease during aging, and increase during chronic stress and use of some prescription drugs.[3]

Absorption, metabolism, excretion[edit]

Animal-sourced food contains protein-bound FMD and FAD. Gastric acid exposure in the stomach frees the coenzymes from the proteins. The coenzymes are enzymatically hydrolyzed in the small intestine to free riboflavin. Absorption occurs via an active, saturable transport system that is rapid and proportional to dose, with some additional passive diffusion occurring at high concentrations. Bile salts facilitate update, so absorption is improved when the vitamin is consumed with a meal.[7][8] One small clinical trial reported that in adults, the maximal amount of riboflavin that can be absorbed from a single dose was 27 mg.[29] The majority of newly absorbed riboflavin is taken up by the liver on 'first pass,' so post-prandial appearance of riboflavin in plasma underestimates absorption.[8] Three riboflavin transporter proteins have been identified. RFVT1 is present in the small intestine and also in the placenta. RFVT2 is highly expressed in brain and salivary glands. RFVT3 is most highly expressed in small intestine and also in testes and prostate.[8] Infants with gene mutations that do not code for these transport proteins can be treated with pharmacological amount of riboflavin.[30]

When riboflavin is absorbed in excess of requirements, the excess is quickly excreted in urine as riboflavin.[8] Urine color is used as a hydration status biomarker, and under normal conditions correlates with urine specific gravity and osmolality.[31] However, riboflavin supplementation in large excess of requirements causes urine to have a more yellow color than normal.[6] With normal dietary intake, about two-thirds of urinary output is riboflavin, the remainder having been partially metabolized to hydroxymethylriboflavin from oxidation within cells, and as other metabolites. When consumption exceeds ability to absorb, bacteria in the large intestine catabolize riboflavin to various metabolites that can be measured in feces.[8]

Deficiency[edit]

Prevalence[edit]

Mild riboflavin deficiencies can exceed 50% of the population in countries with chronic multi-nutrient undernutrition and in acute situations, such as refugee populations.[citation needed] Deficiency is uncommon in the United States and in other countries which have wheat flour or corn meal fortification programs.[27] From data collected in biannual surveys of the U.S. population, for ages 20 and over, 22% of females and 19% of men reported consuming a dietary supplement that contained riboflavin, typically a vitamin/mineral multi-supplement. For the non-supplement users, adult women averaged 1.74 mg/day and men 2.44 mg/day. These amount exceed the RDAs of 1.1 and 1.3 mg/day.[32] For all ages, on average, consumption from food exceeded the RDAs.[33] Results from an older US survey reported that less than 3% of the population consumed less than the Estimated Average Requirement.[34]

Signs and symptoms[edit]

Riboflavin deficiency (also called ariboflavinosis) results in stomatitis including painful red tongue with sore throat, chapped and fissured lips (cheilosis), and inflammation of the corners of the mouth (angular stomatitis). There can be oily scaly skin rashes on the scrotum, vulva, philtrum of the lip, or the nasolabial folds. The eyes can become itchy, watery, bloodshot and sensitive to light. Riboflavin deficiency is associated with anemia.[35] This is distinct from anemia caused by deficiency of folic acid (B9) or cyanocobalamin (B12), which causes anemia with large blood cells (megaloblastic anemia). Deficiency of riboflavin during pregnancy can result in birth defects including congenital heart defects[36] and limb deformities.[37] Prolonged riboflavin insufficiency is also known to cause degeneration of the liver and nervous system.[7]

Causes[edit]

Riboflavin deficiency is usually found together with other nutrient deficiencies, particularly of other water-soluble vitamins. A deficiency of riboflavin can be primary – poor vitamin sources in one's daily diet – or secondary, which may be a result of conditions that affect absorption in the intestine, the body not being able to use the vitamin, or an increase in the excretion of the vitamin from the body. Diet patterns that increase risk of deficiency include veganism and low-dairy vegetarianism.[8] Diseases such as cancer, heart disease and diabetes are also thought to cause or exacerbate riboflavin deficiency.[7]

There are rare genetic defects that compromise riboflavin absorption, transport, metabolism or utilization by flavoproteins. One of these is riboflavin transporter deficiency, previously known as Brown-Vialetto-Van Laere syndrome. Variants of the genes SLC52A2 and SLC52A3 which code respectively, for transporter proteins RDVT2 and RDVT3 are defective. Infants and young children present with muscle weakness, cranial nerve deficits including hearing loss, sensory symptoms including sensory ataxia, feeding difficulties and respiratory difficulties which are caused by a sensorimotor axonal neuropathy and cranial neuropathy. When untreated, most infants with riboflavin transporter deficiency rapidly become ventilator dependent and die in the first decade of life. Treatment with oral supplementation of high amounts of riboflavin is lifesaving.[30][38]

Other inborn errors of metabolism include riboflavin-responsive multiple acyl-CoA-dehydrogenase deficiency, also known as a subset of glutaric acidemia type 2, and the C677T variant of the methylenetetrahydrofolate reductase enzyme, which in adults has been associated with risk of high blood pressure.[8]

Diagnosis[edit]

Riboflavin deficiency is also known as ariboflavinosis. The assessment of riboflavin status is essential for confirming cases with non-specific symptoms whenever deficiency is suspected. Indicators that have been used in humans are erythrocyte glutathione reductase, erythrocyte flavin concentration and urinary excretion, the last with either a normal urine sample or after a vitamin load test.[7][8] Erythrocyte glutathione reductase (EGR) is a flavin-adenine dinucleotide (FAD)-dependent enzyme, and the major flavoprotein in erythrocytes. Measurement of the activity coefficient of EGR is the preferred method for assessing riboflavin status. It provides a measure of tissue saturation and long-term riboflavin status. Fresh red blood cells are washed, lysed and assayed. Results are expressed as an activity coefficient (AC), a ratio, determined by enzyme activity with and without the addition of FAD) to the culture medium. An AC of 1.0 to 1,2 indicates that adequate amounts of riboflavin were present; 1.2 to 1.4 is considered low, greater than 1.4 indicates deficient.[8] With the erythrocyte flavin method, values greater than 400 nmol/L are considered adequate and values below 270 nmol/l deficient. This is not considered as sensitive as the EGR method.[7] Urinary excretion is expressed as nmol of riboflavin per gram of creatinine. Low is in range of 50 to 72 nmol/g and deficient is below 50 nmol/g. Load tests provided evidence for determining dietary requirements. For adult men, as oral doses were increased from 0.5 mg to 1.1 mg, there was a modest linear increase in urinary riboflavin, reaching 100 micrograms in a subsequent 24-hour urine collection. Beyond a load dose of 1.1 mg, urinary excretion increased rapidly, so that with a dose of 2.5 mg, urinary content was 800 micrograms.[7]

History[edit]

The name "riboflavin" comes from "ribose" (the sugar whose reduced form, ribitol, forms part of its structure) and "flavin", the ring-moiety which imparts the yellow color to the oxidized molecule (from Latin flavus, "yellow").[4] The reduced form, which occurs in metabolism along with the oxidized form, appears as orange-yellow needles or crystals.[9]

"Vitamin B" was originally considered to have two components, a heat-labile vitamin B1 and a heat-stable vitamin B2.[2] In the 1920s, vitamin B2 was initially thought to be the factor necessary for preventing pellagra.[2] In 1923, Paul Gyorgy in Heidelberg was investigating egg-white injury in rats;[2] the curative factor for this condition was called vitamin H, which is now called biotin. Since both pellagra and vitamin H deficiency were associated with dermatitis, Gyorgy decided to test the effect of vitamin B2 on vitamin H deficiency in rats. He enlisted the service of Wagner-Jauregg in Kuhn's laboratory.[2] In 1933, Kuhn, Gyorgy, and Wagner found that thiamin-free extracts of yeast, liver, or rice bran prevented the growth failure of rats fed a thiamin-supplemented diet.[2]

Further, the researchers noted that a yellow-green fluorescence in each extract promoted rat growth, and that the intensity of fluorescence was proportional to the effect on growth.[2] This observation enabled them to develop a rapid chemical and bioassay to isolate the factor from egg white in 1933.[2] The same group then isolated the same preparation (a growth-promoting compound with yellow-green fluorescence) from whey using the same procedure (lactoflavin). In 1934, Kuhn's group identified the structure of so-called flavin and synthesized vitamin B2, leading to evidence in 1939 that riboflavin was essential for human health.[2]

Riboflavin deficiency caused stomatitis symptoms similar to those seen in pellagra, which is due to niacin deficiency. For this reason, early in the history of identifying riboflavin, the consequences of deficiency were sometimes called "pellagra sine pellagra" (pellagra without pellagra), because it caused stomatitis but not widespread peripheral skin lesions characteristic of niacin deficiency.[39] Around the same time, the vitamin was also referred to as "Vitamin G."[40]

See also[edit]

References[edit]

  1. ^ a b c d "Riboflavin". Drugs.com. 1 July 2021. Retrieved 8 October 2021.
  2. ^ a b c d e f g h i j Northrop-Clewes CA, Thurnham DI (2012). "The discovery and characterization of riboflavin". Annals of Nutrition & Metabolism. 61 (3): 224–30. doi:10.1159/000343111. PMID 23183293. S2CID 7331172.
  3. ^ a b c d e f g h i j k l m n o p q r s "Riboflavin: Fact Sheet for Health Professionals". Office of Dietary Supplements, US National Institutes of Health. 20 August 2018. Retrieved 7 November 2018.
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  5. ^ "What nutrients are added to flour and rice in fortification?". Food Fortification Initiative. 2021. Retrieved 8 October 2021.
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  8. ^ a b c d e f g h i j k l Merrill AH, McCormick DB (2020). "Riboflavin". In BP Marriott, DF Birt, VA Stallings, AA Yates (eds.). Present Knowledge in Nutrition, Eleventh Edition. London, United Kingdom: Academic Press (Elsevier). pp. 189–208. ISBN 978-0-323-66162-1.
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  14. ^ Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E (April 2012). "Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society". Neurology. 78 (17): 1346–53. doi:10.1212/wnl.0b013e3182535d0c. PMC 3335449. PMID 22529203.
  15. ^ ""Natural" remedies for migraine – should I try them?". UK National Migraine Centre. 2021. Retrieved 8 October 2021.
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  17. ^ Sherwood M, Goldman RD (March 2014). "Effectiveness of riboflavin in pediatric migraine prevention". Canadian Family Physician. 60 (3): 244–6. PMC 3952759. PMID 24627379.
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  24. ^ "Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels. FR page 33982" (PDF). Archived (PDF) from the original on 8 August 2016.
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